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Provided by the author(s) and NUI Galway in accordance with publisher policies. Please cite the published version when available. Title Author(s) Anandamide modulation of endotoxin-induced inflammation Kerr, Daniel M.; Henry, Rebecca; Roche, Michelle Publication Date 2013-12-20 Publication Information Kerr DM, Henry R, Roche M (2013) 'Anandamide Modulation of Endotoxin-Induced Inflammation' Anatomy and Physiology, 4:e130. doi: 10.4172/2161-0940.1000e130 Publisher OMICS International Link to publisher's version http://www.omicsonline.org/open-access/anandamidemodulation-of-endotoxininduced-inflammation-21610940.1000e130.php?aid=23483 Item record http://hdl.handle.net/10379/5749 DOI http://dx.doi.org/10.4172/2161-0940.1000e130 Downloaded 2017-05-05T20:49:09Z Some rights reserved. For more information, please see the item record link above. Anatomy & Physiology Kerr et al., Anat Physiol 2013, 4:1 http://dx.doi.org/10.4172/2161-0940.1000e130 Editorial Open Access Anandamide Modulation of Endotoxin-Induced Inflammation Daniel M Kerr, Rebecca Henry and Michelle Roche* Physiology, NCBES Galway Neuroscience Centre and Centre for Pain Research, National University of Ireland Galway, Ireland The endocannabinoid system is comprised of the CB1 and CB2 receptors, the naturally occurring endogenous ligands, anandamide (AEA) and 2-arachidonyl glycerol (2-AG); and the enzymes involved in their synthesis and degradation. The enzyme fatty acid amide hydrolyase (FAAH) preferentially metabolises AEA, and the related N-acylethanolamines, N-palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA). While PEA and OEA do not have activity at CB1/2 receptors, they are capable of enhancing AEA signaling by competing with AEA at the catalytic site on the FAAH enzyme. All elements of the endocannabinoid system are widely and densely expressed in the mammalian immune system and brain and as such represent an important therapeutic target for a number of peripheral and central inflammatory disorders [1-3]. In vitro and in vivo data, has demonstrated that cannabinoid agonists modulate immune function and inflammatory responses in several preclinical animal models including those association with pain, colitis, sepsis and neurodegenerative disorders [4-7]. For example, data from our lab has demonstrated that the potent cannabinoid agonist HU210 attenuates increases in pro-inflammatory cytokine levels, in particular interleukin(IL)-1β, both peripherally and in discrete brain regions, observed following administration of the endotoxin and toll-like receptor 4 agonist lipopolysaccaride (LPS) [5]. The antiinflammatory effects of HU210 were shown to be partially mediated by CB1, but not CB2 receptors. Overt psychotropic effects are associated with the administration of potent synthetic CB1 agonists and as such enhancing endocannabinoid tone has been proposed as an alternative means of activating cannabinoid receptors without such concomitant effects. In vitro studies suggest that endocannabinoids elicit antiinflammatory effects comparable to those of exogenous cannabinoids. Increasing AEA tone, either directly or via inhibition of its degradation or uptake, has been demonstrated to reduce levels of pro-inflammatory cytokines and inflammatory mediators such as tumour necrosis factor (TNF)α, IL-1β and nitric oxide in response to immune stimulation in several in vitro systems [8-14]. In many cases, the attenuation of proinflammatory cytokine responses is paralleled with an increase in the production of anti-inflammatory cytokines, such as IL-10 [12,15]. Recent data indicates that neuroprotective effects of AEA may be mediated by IL-10 induced increases in the expression of CD200 [16], a membrane glycoprotein expressed on neurons that suppresses immune activity by interacting with its receptor on microglia. However, it should be noted that enhancing AEA tone has also been demonstrated to enhance IL-6 levels in astrocyte culture preparations [10,17]. In addition, genetic deletion of FAAH in astrocytes exacerbated their inflammatory phenotype against β-amyloid [14]. Thus, AEA may attenuate or enhance inflammatory reactions depending on the conditions under investigation. In vitro data has provided us with an understanding of the molecular and cellular mechanism underlying the effects of AEA, effects which have now been substantiated in several in vivo models. Data from our group and others have demonstrated enhanced AEA levels in several animal models including those relating to autism [18], inflammatory and neuropathic pain [19,20], Parkinson’s disease [21] and Multiple sclerosis [22], disorders with a well characterized inflammatory component. Data from our group has provided some of the first evidence of an immunomodulatory role Anat Physiol ISSN:2161-0940 Physiol, an open access journal for enhanced anandamide tone in vivo following systemic bacterial endotoxin administration. We demonstrated that inhibition of AEA degradation following administration of the FAAH inhibitor URB597, potentiated LPS-induced increases in TNFα levels in plasma [23]. Similarly, systemic administration of the endocannabinoid re-uptake inhibitor AM404, augmented LPS-induced increases in TNFα levels while concurrently attenuating plasma IL-1β and IL-6 levels [23]. On investigation of the receptor mechanisms underlying this effect, we revealed that the AM404-induced attenuation of IL-1β was prevented by antagonism of the CB1 receptor. In comparison, antagonism of CB1, CB2, PPARγ and TRPV1 receptors attenuated the AM404-induced potentiation of TNFα following LPS administration [23] indicating possible involvement of one or all of the aforementioned receptors in this response. In accordance with this data, De Laurentiis and coworkers demonstrated that AEA activation of hypothalamic CB1 receptors facilitates LPS-induced increases in plasma TNFα levels [24]. Examination of the effects of AEA on central inflammatory responses has revealed that enhancing AEA tone attenuates microglial activation and pro-inflammatory cytokine expression in several neuroinflammatory animals models [15,25-27]. Recent data from our lab has demonstrated that systemic administration of URB597 enhances central AEA levels and attenuates LPS-induced increase in IL-1β expression while concurrently augmenting suppressor of cytokine signalling (SOCS)3 (and tended to do so also for IL-6) expression in the hypothalamus [28]. AEA modulation of endotoxin-induced cytokine changes in the hypothalamus may ameliorate the associated sickness response, including changes in body temperature, hypophagia, hypothalamicpituitary-adrenal (HPA) axis activation and hyperalgesia. Recent evidence has demonstrated that AEA attenuates LPS-induced fever and hypophagia [29], most likely via modulation of hypothalamic cytokine expression. Furthermore, central AEA has been shown to increase, while CB1 receptor antagonism attenuates, LPS-induced hypothermia [30], further demonstrating a role for AEA-CB1 in modulation of thermal responses to systemic inflammation. Increasing evidence demonstrates that endocannabinoids act to inhibit stress-induced HPA axis activation [31]. Our data demonstrated that enhanced AEA tone following URB597 failed to alter LPS-induced increases in plasma corticosterone levels [28]. Hypothalamic TNFα may underlie the LPSinduced increase in plasma corticosterone, an effect not altered by URB597. In addition, pharmacological and genetic FAAH inhibition has been shown to reduce LPS-induced nociceptive behaviour tactile allodynia, oedema and associated increases in IL-1β and TNFα levels, *Corresponding author: Michelle Roche, Physiology, National University of Ireland Galway, University Road, Galway, Ireland, Tel: +353 91 495427; E-mail: [email protected] Received December 17, 2013; Accepted December 18, 2013; Published December 20, 2013 Citation: Kerr DM, Henry R, Roche M (2013) Anandamide Modulation of EndotoxinInduced Inflammation. Anat Physiol 4: e130. doi:10.4172/2161-0940.1000e130 Copyright: © 2013 Kerr DM, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Volume 4 • Issue 1 • 1000e130 Citation: Kerr DM, Henry R, Roche M (2013) Anandamide Modulation of Endotoxin-Induced Inflammation. Anat Physiol 4: e130. doi:10.4172/21610940.1000e130 Page 2 of 2 effects attributed to AEA activity at CB1 and/or CB2 receptors [32,33]. While the immunomodulatory effects of FAAH inhibition have been attributed primarily to AEA activation of CB1 receptors, it is worth noting that associated changes in N-acylethanalomines may account, at least in part, for some of the non-CB1/2 receptor mediated effects observed. 16.Hernangómez M, Mestre L, Correa FG, Loría F, Mecha M, et al. (2012) CD200CD200R1 interaction contributes to neuroprotective effects of anandamide on experimentally induced inflammation. Glia 60: 1437-1450. In conclusion, increasing evidence support an important role for AEA in modulation of (neuro) inflammatory responses to endotoxin exposure. Given the lack of psychotropic effects and abuse liability associated with FAAH inhibition, modulation of AEA tone via this means represents an important therapeutic target for inflammatory disorders. 18.Kerr DM, Downey L, Conboy M, Finn DP, Roche M (2013) Alterations in the endocannabinoid system in the rat valproic acid model of autism. Behav Brain Res 249: 124-132. Acknowledgements 20.Roques BP, Fournié-Zaluski MC, Wurm M (2012) Inhibiting the breakdown of endogenous opioids and cannabinoids to alleviate pain. Nat Rev Drug Discov 11: 292-310. Funding provided by Science Foundation Ireland Research Frontiers Project (Grant no. 11/RFP/NES/3175) and the Discipline of Physiology, National University of Ireland Galway. References 1. 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Biochem Pharmacol 77: 86-100. 14.Benito C, Tolón RM, Castillo AI, Ruiz-Valdepeñas L, Martínez-Orgado JA, et al. (2012) β-Amyloid exacerbates inflammation in astrocytes lacking fatty acid amide hydrolase through a mechanism involving PPAR-α, PPAR-γ and TRPV1, but not CBâ‚ or CBâ‚‚ receptors. Br J Pharmacol 166: 1474-1489. 15.Correa F, Hernangomez-Herrero M, Mestre L, Loria F, Docagne F, et al. (2011) The endocannabinoid anandamide downregulates IL-23 and IL-12 subunits in a viral model of multiple sclerosis: evidence for a cross-talk between IL-12p70/ IL-23 axis and IL-10 in microglial cells. Brain Behav Immun 25: 736-749. Anat Physiol ISSN:2161-0940 Physiol, an open access journal 29.Hollis JH, Jonaidi H, Lemus M, Oldfield BJ (2011). The endocannabinoid arachidonylethanolamide attenuates aspects of lipopolysaccharide-induced changes in energy intake, energy expenditure and hypothalamic Fos expression. J Neuroimmunol 233: 127-134. 30.Steiner AA, Molchanova AY, Dogan MD, Patel S, Pétervári E, et al. (2011) The hypothermic response to bacterial lipopolysaccharide critically depends on brain CB1, but not CB2 or TRPV1, receptors. J Physiol 589: 2415-2431. 31.Hill MN, Tasker JG (2012) Endocannabinoid signaling, glucocorticoid-mediated negative feedback, and regulation of the hypothalamic-pituitary-adrenal axis. Neuroscience 204: 5-16. 32.Booker L, Kinsey SG, Abdullah RA, Blankman JL, Long JZ, et al. (2012) The fatty acid amide hydrolase (FAAH) inhibitor PF-3845 acts in the nervous system to reverse LPS-induced tactile allodynia in mice. Br J Pharmacol 165: 24852496. 33.Naidu PS, Kinsey SG, Guo TL, Cravatt BF, Lichtman AH (2010) Regulation of inflammatory pain by inhibition of fatty acid amide hydrolase. J Pharmacol Exp Ther 334: 182-190. Citation: Kerr DM, Henry R, Roche M (2013) Anandamide Modulation of Endotoxin-Induced Inflammation. Anat Physiol 4: e130. doi:10.4172/21610940.1000e130 Volume 4 • Issue 1 • 1000e130